Anophthalmia is a severe congenital eye malformation characterized by the complete absence of ocular tissue within the orbit. It occurs at a frequency of 0.6 to 4.2 per 100,000 live births1). The estimated birth prevalence is about 3 per 100,0002).
Clinically, it is divided into the following two types:
Anophthalmia forms a continuous spectrum with microphthalmia. In microphthalmia, a hypoplastic eye is present within the orbit. Clinically, differentiation between severe microphthalmia and anophthalmia can be difficult and requires imaging studies7).
Anophthalmia may occur in isolation or as part of a syndrome. It is reported to be bilateral in 53–71% of cases. The rate of associated systemic abnormalities is high, with 32–93% of cases involving other organ anomalies2).
Anophthalmia is the complete absence of ocular tissue. Microphthalmia is the presence of a hypoplastic eye. They form a continuous spectrum, and differentiation from severe microphthalmia requires imaging such as MRI7).
Anophthalmia is a congenital condition, so the affected child has no subjective symptoms. The guardian notices the absence of the eyeball at birth.
Clinical findings after birth are as follows:
In bilateral cases, depressed orbits and midface hypoplasia are observed5).
The etiology of anophthalmia is complex, involving both genetic and environmental factors.
Over 90 genes have been reported to be associated with anophthalmia and microphthalmia 2). The main causative genes are as follows.
SOX2
Most frequent causative gene: accounts for 10–20% of severe bilateral cases 1).
Inheritance pattern: mostly de novo heterozygous loss-of-function mutations.
SOX2 anophthalmia syndrome: may be accompanied by learning disabilities, growth retardation, epilepsy, esophageal atresia, and genitourinary abnormalities 1).
OTX2
Second most common causative gene: found in about 3% of bilateral anophthalmia cases.
Function: encodes a transcription factor that regulates optic vesicle differentiation and retinal formation.
Extraocular manifestations: associated with pituitary abnormalities (growth hormone deficiency), learning disabilities, and brain structural abnormalities 6).
Other important genes include:
Chromosomal abnormalities such as trisomy 13, trisomy 18, and mosaic trisomy 9 are associated 1). 14q22q23 microdeletion syndrome (Frias syndrome) presents with anophthalmia and pituitary abnormalities due to deletion of BMP4 and OTX2 6).
According to a review by Goyal et al. (2025), all Mendelian inheritance patterns—autosomal dominant, autosomal recessive, and X-linked—have been reported in anophthalmia and microphthalmia. Most cases occur sporadically due to de novo mutations 2).
The following intrauterine environmental factors have been reported 1)2):
The following epidemiological risk factors are known:
Anophthalmia can be detected prenatally by ultrasound examination 1).
However, it is rarely detected by prenatal ultrasound unless other abnormalities coexist.
Postnatal diagnosis is performed as follows.
| Imaging study | Main evaluation target | Characteristics |
|---|---|---|
| Ultrasound | Presence of eyeball, axial length | Noninvasive, simple |
| MRI | Optic nerve, central nervous system abnormalities | Detailed soft tissue evaluation |
| CT | Orbital bone structure | Excellent for bone evaluation |
MRI confirms complete absence of the eyeball and optic nerve hypoplasia. Extraocular muscles may be present even without an eyeball5).
Because of the possibility of syndromic involvement, comprehensive genetic testing is recommended1).
The following are performed as screening for associated abnormalities:
Alhubaishi et al. (2024) reported a case of bilateral congenital anophthalmia in which brain MRI suggested a Dandy-Walker variant and left renal pelvis dilation was noted5). This case illustrates the importance of systemic evaluation in the management of anophthalmia.
It may be detectable prenatally by ultrasound from around 12 weeks of gestation. However, prenatal diagnosis is difficult unless other abnormalities coexist, and it is often discovered after birth during clinical examination1). MRI is useful for definitive diagnosis.
Treatment for anophthalmia is not aimed at restoring vision, but at promoting normal orbital development, maintaining facial symmetry, and enabling the fitting of an ocular prosthesis.
Early intervention from infancy is essential. The normal infant eye is about 70% of adult size and grows most rapidly during the first 12 months of life 3). Without mechanical stimulation of the orbit during this period, orbital development is delayed, leading to facial asymmetry.
This is the least invasive initial treatment and should ideally be started within 1–2 weeks after birth 3).
Yamashita et al. (2023) reported orbital expansion using a thermoplastic resin splint in a 2-month-old infant with clinical congenital anophthalmia. The splint was replaced stepwise as the child grew, and after 5 years, there was almost no difference between the orbits, indicating a good outcome 3). This report demonstrates the usefulness of a material that can be easily fabricated in an outpatient setting.
This is considered about 2 months after conformer placement.
Kato-Junior et al. (2025) reported a new technique combining dermis fat graft with upper eyelid skin graft in three children with unilateral congenital anophthalmia. Better outcomes were obtained in two cases where surgery was performed within the first month of life, highlighting the importance of early intervention 4).
Conformer
Invasiveness: Low. Can be fitted and replaced in an outpatient setting.
Start timing: Ideally 1–2 weeks after birth.
Advantages: Non-surgical and allows repeated expansion.
Disadvantages: Requires frequent replacement. May be insufficient in severe cases.
Orbital Implant
Invasiveness: Requires surgery.
Start timing: Several months after conformer therapy.
Advantages: Permanent increase in orbital volume. DFG grows with the child.
Disadvantages: Risk of exposure and infection. Requires staged replacement.
After the orbit is sufficiently expanded, a prosthetic eye (external prosthesis) is fitted. Transition to a standard prosthetic eye may be possible after 8 months of age 3). Adjustment is needed about once a year as the child grows. When introducing a prosthetic eye in children, the number of adjustments may be 3 or more, and the adjustment period may exceed 6 months. In principle, prosthetic eyes for microphthalmia are not covered by insurance, and the financial burden on families is significant.
The following additional surgeries may be considered to improve overall appearance.
Orbital expansion treatment with a conformer is started early in life, and after the conjunctival sac has sufficiently developed, transition to a prosthetic eye is made. The timing varies by case, but it may be possible from around 8 months of age 3). The size of the prosthetic eye needs to be adjusted periodically as the child grows.
The eye is formed through a highly coordinated series of steps involving tissues derived from the neuroectoderm, neural crest cells, mesoderm, and surface ectoderm.
Anophthalmia is classified into three types based on the timing of developmental disturbance.
| Classification | Timing of occurrence | Characteristics |
|---|---|---|
| Primary | Before optic vesicle formation | Rare. Usually bilateral. |
| Secondary | Neural tube formation period | Secondary to anterior neural tube abnormalities. Lethal. |
| Consecutive | After optic vesicle formation | Due to secondary degeneration of the optic vesicle. |
Multiple transcription factors and signaling pathways are involved in ocular development2).
According to a review by Goyal et al. (2025), the extracellular matrix (ECM) also plays an important role in eye development. Impairment of laminin subunits causes ocular malformations, and lumican (LUM) regulates axial length. Type IV collagen mutations affect retinal pigment epithelium growth2).
In addition to genetic mutations, epigenetic modifications are also involved in the development of anophthalmia2).
The widespread use of whole exome sequencing (WES) and whole genome sequencing (WGS) has enabled the identification of rare genetic variants that were previously difficult to detect2).
Harding et al. (2023) conducted a molecular diagnostic study of 50 MAC cohort cases and identified pathogenic variants in approximately 33% using comprehensive analysis with targeted gene panels, WGS, and microarray CGH. New genotype-phenotype correlations were also reported, such as the association of EPHA2 with microphthalmia and FOXE3 with hearing impairment and renal abnormalities2).
Efforts are underway to apply WES as a precise test for prenatal ultrasound abnormalities. Even in cases difficult to diagnose with conventional karyotyping or microarray, reports indicate that WES can provide an additional diagnosis in 6.2–57% of cases 2).
Research using induced pluripotent stem cells (iPSCs) is opening new therapeutic possibilities 2).
A workflow for fabricating conformers using computer-aided design (CAD) and 3D printing has been developed, offering the potential for personalized and precise treatment.
Genetic testing is useful for elucidating the cause, predicting complications, and genetic counseling. It is especially recommended when bilateral or syndromic cases are suspected 1). However, in about 67% of cases, pathogenic mutations may not be identified even with current technology, so involvement of a clinical genetic specialist is important for interpreting results.
- Russo M, Palmeri S, Zucconi A, Vagge A, Arioni C. Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review. Ital J Pediatr. 2025;51:65.
- Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr. 2025;14(2):101982.
- Yamashita K, Yotsuyanagi T, Hamamoto Y, Gonda A, Kita A, Kitada A. Enlargement of the Eye Socket Early after Birth with an Ocular Prosthesis for Clinical Congenital Anophthalmia. J Plast Recontr Surg. 2023;2(1):20-24.
- Kato-Junior EM, Padovani CR, Meneghim RLFS, Schellini SA. Congenital anophthalmia treated with a dermis fat graft combined with a skin graft in the upper lid in early childhood. Saudi J Ophthalmol. 2025;39:275-277.
- Alhubaishi F, Almedfaa A, Andacheh M. A Case of Congenital Bilateral Anophthalmia. Curr Health Sci J. 2024;50(2):328-331.
- Kera J, Watal P, Ali SA. Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome. Cureus. 2021;13(7):e16395.
- Dedushi K, Hyseni F, Musa J, et al. A rare case of anophthalmia without any family history and antenatal risk factors. Radiol Case Rep. 2021;16:3772-3775.
- Lu Y, Zhao JJ, He P. A 12 Week Fetus with Anophthalmia, Limb Anomalies and Infratemporal Teratoma. Int J Womens Health. 2024;16:41-46.
- Rasic DM, Vasovic DD, Knezevic M. Primary Orbital Teratoma With Congenital Anophthalmia in a Neonate: A Rare Case With Histopathological and Radiological Correlation. Case Rep Ophthalmol Med. 2025;2025:5032089.
- Chen D, Heher K. Management of the anophthalmic socket in pediatric patients. Curr Opin Ophthalmol. 2004;15:449-453.
